1. Field of the Invention
The present invention relates to 1-phenylpyrrole compounds, to atropisomers thereof, and to such compounds as preventive or therapeutic drugs and their uses for the prevention or treatment of hypertension, angina pectoris, acute coronary syndrome, congestive heart failure, nephropathy, including diabetic nephropathy, arteriosclerosis, cerebral infarction, fibrosis, primary aldosteronism and edema, which compounds have exceptional mineralocorticoid receptor antagonist activity.
2. Summary of the Related Art
Mineralocorticoid receptor (MR) (aldosterone receptor) is known to play an important role in controlling electrolyte balance in the body and blood pressure (for example, Advances in Physiology Education, 26 (1): 8-20 (2002)), and mineralocorticoid receptor antagonist such as spironolactone and eplerenone having a steroid structure is known to be useful for treating hypertension and heart failure (for example, Clinical Science and molecular medicine. 3 (Suppl), 329s-332s (1976); and Clinical Science and molecular medicine. 45 (Suppl 1), 219s-224s (1973)).
Hypertension is not only a primary cause of the development of cardiovascular, cardiac and renal diseases, but a risk factor for the progression of these diseases initiated by other mechanisms such as atherosclerosis, cardiovascular disease, ischemic heart disease, diabetes, diabetic nephropathy, chronic glomerulonephritis and polycystic kidney disease (J. Am. Soc. Nephrol., 14:2395-2401 (2003)).
In renal failure, as with the case of chronic heart failure, a number of clinical trials have established that interruption of the RAAS cascade with ACE inhibitors is beneficial in limiting renal disease (Am. J. Kid. Dis., 37 (4): 677-688 (2001). Additional studies have also established that aldosterone antagonists can attenuate proteinuria and renal damage typically observed in progressive renal disease and offer further therapeutic benefit compared to ACE inhibitors alone (Hypertension., 31:451-458 (1998)).
However, spironolactone has low selectivity for MR, and side effects such as menstrual irregularity in women and gynecomastia in men are reported (e.g., Circulation, 107, 2512-2518 (2003)). In contrast, since eplerenone has relatively weak effect against MR (for example, Nature Reviews, 2, 177-178 (2003)) and thus induces hyperkalemia, it is not suitable for patients having renal failure.
Here, as a mineralocorticoid receptor antagonist having a non-steroidal skeleton, pyrrole derivatives described in pamphlet of International Publication No. WO 2006/012642 have been known; however, atropisomers of a compound represented by the general formula (I) of the present invention have not been known.